A systems genetics approach delineates the role of Bcl2 in leukemia pathogenesis

Leukemia is a group of malignancies of the blood forming tissues, and is characterized by the uncontrolled proliferation of blood cells. In the United States, it accounts for approximately 3.5% and 4% of all cancer-related incidences and mortalities, respectively. The current study aimed to explore the role of Bcl2 and associated genes in leukemia pathogenesis using a systems genetics approach. The transcriptome data from BXD Recombinant Inbred (RI) mice was analyzed to identify the expression of Bcl2 in myeloid cells. eQTL mapping was performed to select the potential chromosomal region and subsequently identify the candidate gene modulating the expression of Bcl2. Furthermore, gene enrichment and protein-protein interaction (PPI) analyses of the Bcl2-coexpressed genes were performed to demonstrate the role of Bcl2 in leukemia pathogenesis. The Bcl2-coexpressed genes were found to be enriched in various hematopoietic system related functions, and multiple pathways related to signaling, immune response, and cancer. The PPI network analysis demonstrated direct interaction of hematopoietic function related genes, such as Bag3, Bak1, Bcl2l11, Bmf, Mapk9, Myc, Ppp2r5c, and Ppp3ca with Bcl2. The eQTL mapping identified a 4.5 Mb genomic region on chromosome 11, potentially regulating the expression of Bcl2. A multi-criteria filtering process identified Top2a, among the genes located in the mapped locus, as the best candidate upstream regulator for Bcl2 expression variation. Hence, the current study provides better insights into the role of Bcl2 in leukemia pathogenesis and demonstrates the significance of our approach in gaining new knowledge on leukemia. Furthermore, our findings from the PPI network analysis and eQTL mapping provide supporting evidence of leukemia-associated genes, which can be further explored for their functional importance in leukemia. DATA AVAILABILITY: The myeloid cell transcriptomic data of the BXD mice used in this study can be accessed through our GeneNetwork (http://www.genenetwork.org) with the accession number of GN144.